Pre-clinical studies in experimental animals have yielded a large array of antibodies capable of inducing anti-tumor immunity in animal models. However, in most cases, progress has been slow in translating the principles learned in animal models into therapy of human cancer. A common obstacle to successful clinical translation is that biological properties of the antibodies specific for given human target molecules cannot be pre-screened in vivo prior to clinical trials. Here we propose to use costimulatory molecule CTLA-4 as a model target to develop a paradigm for screening anti-cancer antibodies for clinical trials. Recent studies have demonstrated that anti-CTLA4 mAbs induce T cell immunity against a variety of cancers in experimental animals. We will use mice with a knock-in ofhuman (hu) CTLA4 gene about to screen for anti-huCTLA4 antibodies that can induce anti-tumor immunity in mice. Those anti-CTLA4 mAbs that induce cancer rejection will be modified for clinical trials in the phase II application. Moreover, our proposed studies may provide a paradigm for the development of antibodies specific for human target molecules with a potential for clinical application. PROPOSED COMMERCIAL APPLICATION: The antibodies screened in the CTLA4 knock-in mice will be capable of inducing immunity by engaging human CTLA4 molecules. Given the success that several laboratories have had in the mouse, it is likely that anti-human CTLA4 mAb may induce immunity to multiple lineages of cancer. Moreover, the CTLA4 knock-mice will provide a valuable tool for the production of therapeutic anti-human CTLA4 monoclonal antibodies.